US4177272A - Disubstituted piperazines - Google Patents

Disubstituted piperazines Download PDF

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US4177272A
US4177272A US05/864,204 US86420477A US4177272A US 4177272 A US4177272 A US 4177272A US 86420477 A US86420477 A US 86420477A US 4177272 A US4177272 A US 4177272A
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piperazine
thiadiazol
benzo
methyl
compound
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Gilbert Regnier
Roger Canevari
Michel Laubie
Jean-Claude Poignant
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Science Union et Cie
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms

Definitions

  • the present invention provides disubstituted piperazines of the formula I: ##STR3## and acid addition salts, especially physiologically tolerable acid addition salts thereof,
  • A is selected from the group consisting of a benzene ring, and 5-, 6- and 7-membered heterocyclic rings having one and two double bonds and one and two hetero atoms selected from oxygen and sulfur atoms, so that the group ##STR4## is selected from the group consisting of naphthyl, benzo [b] furanyl, benzo [b] thienyl, benzodioxolyl, benzodioxanyl, benzodioxacycloheptanyl, coumaranyl, chromanyl, ⁇ 3 -chromenyl, thiochromanyl and ⁇ 3 -thiochromenyl radicals,
  • X is a nitrogen atom and simultaneously Y is selected from the group consisting of an oxygen atom and a sulfur atom, or
  • X is selected from the group consisting of a sulfur atom, an amino radical (NH) and a methylimino radical (NCH 3 ), and simultaneously Y is a nitrogen atom, and
  • R is selected from the group consisting of a hydrogen atom, an alkyl radical having from 1 to 5 carbon atoms inclusive, a phenyl radical, halophenyl radicals, alkylphenyl and alkoxyphenyl radicals wherein the alkyl moieties have from 1 to 5 carbon atoms inclusive.
  • the halogen atoms may be, for example, chlorine, fluorine or bromine atoms
  • the alkyl moieties may be methyl, ethyl, propyl, butyl or pentyl radicals and the alkoxy moieties may be methoxy, ethoxy, propoxy, butoxy and pentyloxy radicals.
  • the preferred compounds are the compounds of the formula I wherein A is as defined above, X is a sulfur atom, Y is a nitrogen atom and R is a hydrogen atom, and physiologically tolerable acid addition salts thereof.
  • the most interesting compounds are those having the formula I wherein X, Y and R are as defined in the above paragraph and ##STR5## is selected from the group consisting of benzo [b] furanyl, benzodioxolyl, benzodioxanyl and coumaranyl radicals, and physiologically tolerable acid addition salts thereof.
  • the present invention provides a process for preparing a compound of the general formula I which comprises:
  • a polar solvent for example an alcohol having a high boiling point, for example butanol or pentanol, or preferably an aliphatic amide, for example dimethyl formamide.
  • the processes are advantageously carried out at a temperature of from 110° to 140° C. in the presence of an acceptor for the hydrogen halide formed in the course of the reaction.
  • alkali metal and alkaline-earth metal salts of carbonic acid for example sodium and potassium bicarbonates and carbonates and calcium carbonate
  • organic bases for example dimethylamine, pyridine and triethylamine
  • the present invention also provides a process for preparing a compound of the general formula I which comprises submitting a mixture of an aldehyde of the general formula VI: ##STR10## in which A has the meaning given above, and a N-monosubstituted piperazine of the general formula III given above, to an alkylating reduction using hydrogen at a pressure of from 5 to 7 atmospheres, in the presence of a small quantity of palladium-on-charcoal in a slightly polar aprotic solvent, for example, ethyl acetate.
  • Such a process is advantageously carried out by submitting to hydrogenation under a hydrogen pressure of from 5 to 7 atmospheres, a substantially equimolecular mixture of the compounds of the formulae III and VI, in solution in ethyl acetate, in the presence of a quantity of palladium-on-charcoal such that the weight of palladium is from 0.15 to 0.2% of the total weight of the reactants of the formulae III and VI at a temperature of from 50° to 80° C.
  • the starting materials used for these processes are known compounds, or they may be prepared according to methods described in the literature for preparing similar compounds, as mentioned in the following examples.
  • the compounds of the general formula I are weak bases which may be converted by treatment with acids into acid addition salts.
  • acids which may be used for the formation of these addition salts there may be mentioned for example, in the mineral series: hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and in the organic series: acetic, propionic, maleic, fumaric, tartaric, citric, oxalic, benzoic, methanesulphonic and isethionic acids.
  • the compounds of the formula I may be purified by physical methods, for example by distillation, crystallization or chromatography, or by chemical methods, for example by formation of an addition salt followed by crystallization of the latter and decomposition thereof with an alkaline agent.
  • the compounds of the general formula I possess valuable pharmacological and therapeutic properties, especially anti-hypertensive, peripheral vasodilating, dopaminergic agonistic and anti-Parkinson properties. They may therefore, be used as medicines, especially in the treatment of hypertension, peripheral vascular disorders and Parkinson's disease.
  • mice Their toxicity is low and their LD 50 determined in mice by intraperitoneal route is higher than 200 mg/kg.
  • mice In mice, the average effective dose is about 50 mg/kg by intraperitoneal route. At this dose, there were observed a decrease of motility and tonus.
  • the scores of CNS stimulation or stereotypy were determined according to the method of Quinton and Halliwell, Nature 200 No. 4902, p. 178 (1963). The scores for 3 hours raised up to 246 with a dose of 40 mg/kg I.P. and up to 261 with a dose of 80 mg/kg I.P.
  • the present invention therefore provides a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a compound of the general formula I or a physiologically tolerable acid addition salt thereof in admixture or conjunction with a pharmaceutically suitable carrier, such for example, as distilled water, glucose, lactose, starch, talc, magnesium stearate, ethyl cellulose or cocoa butter.
  • a pharmaceutically suitable carrier such for example, as distilled water, glucose, lactose, starch, talc, magnesium stearate, ethyl cellulose or cocoa butter.
  • compositions are advantageously in unit dosage form and may contain from 30 to 100 mg of the active ingredient.
  • compositions may be in form of tablets, dragees, capsules, suppositories, injectable or drinkable solution and may be administered by oral, rectal or parenteral route at a dose of 30 to 100 mg, 1 to 5 times a day.
  • the reaction mixture was heated at 120° C. for 10 hours. Then, the sodium chloride formed was filtered off and the dimethylformamide was evaporated off under reduced pressure. The residue was taken up in 100 ml of benzene and 100 ml of water; the organic layer was decanted off and the solvent was evaporated off under reduced pressure. There were obtained 10 g of crystals which were recrystallized from 20 ml of ethanol. There were finally obtained 5.6 g of 1-piperonyl-4-(1,3,4-thiadiazol-2-yl)-piperazine melting at 111°-112° C.
  • the starting 1-(1,3,4-thiadiazol-2-yl)-piperazine was prepared by hydrolyzing with alcoholic potassium hydroxide the crude formyl derivative, itself prepared by condensing 1-formyl piperazine with 2-bromo-1,3,4-thiadiazole melting at 74° C. (Goerdeler and al., Ber 89 1534 (1956)).
  • piperonyl chloride and 1-(1,2,4-triazol-3-yl)-piperazine or 1-piperonyl-piperazine and 3-bromo-1,2,4-triazole (cf. Manchot and Noll, Lieb. Ann. 343 9 (1905)), or 3,4-methylenedioxybenzaldehyde and 1-(1,2,4-triazol-3-yl)-piperazine.

Abstract

Disubstituted piperazines of the formula: ##STR1## wherein: ##STR2## is naphthyl, benzo [b] furanyl, benzo [b] thienyl, benzodioxolyl, benzodioxanyl, benzodioxacycloheptanyl, coumaranyl, chromanyl, Δ3 -chromenyl, thiochromanyl or Δ3 -thiochromenyl,
X is nitrogen and simultaneously Y is oxygen or sulfur, or
X is sulfur, imino (NH) or methylimino (N CH3) and simultaneously Y is nitrogen, and
R is hydrogen, lower alkyl, phenyl, halophenyl, lower-alkylphenyl or lower alkoxyphenyl.
These compounds possess interesting pharmacological and therapeutic properties, and may be used as medicines, especially in the treatment of hypertension, peripheral vascular disorders and Parkinson's disease.

Description

The present invention provides disubstituted piperazines of the formula I: ##STR3## and acid addition salts, especially physiologically tolerable acid addition salts thereof,
wherein:
A is selected from the group consisting of a benzene ring, and 5-, 6- and 7-membered heterocyclic rings having one and two double bonds and one and two hetero atoms selected from oxygen and sulfur atoms, so that the group ##STR4## is selected from the group consisting of naphthyl, benzo [b] furanyl, benzo [b] thienyl, benzodioxolyl, benzodioxanyl, benzodioxacycloheptanyl, coumaranyl, chromanyl, Δ3 -chromenyl, thiochromanyl and Δ3 -thiochromenyl radicals,
X is a nitrogen atom and simultaneously Y is selected from the group consisting of an oxygen atom and a sulfur atom, or
X is selected from the group consisting of a sulfur atom, an amino radical (NH) and a methylimino radical (NCH3), and simultaneously Y is a nitrogen atom, and
R is selected from the group consisting of a hydrogen atom, an alkyl radical having from 1 to 5 carbon atoms inclusive, a phenyl radical, halophenyl radicals, alkylphenyl and alkoxyphenyl radicals wherein the alkyl moieties have from 1 to 5 carbon atoms inclusive.
In the meaning of R, the halogen atoms may be, for example, chlorine, fluorine or bromine atoms, the alkyl moieties may be methyl, ethyl, propyl, butyl or pentyl radicals and the alkoxy moieties may be methoxy, ethoxy, propoxy, butoxy and pentyloxy radicals.
Due to their pharmacological properties, the preferred compounds are the compounds of the formula I wherein A is as defined above, X is a sulfur atom, Y is a nitrogen atom and R is a hydrogen atom, and physiologically tolerable acid addition salts thereof.
Among these preferred compounds, the most interesting compounds are those having the formula I wherein X, Y and R are as defined in the above paragraph and ##STR5## is selected from the group consisting of benzo [b] furanyl, benzodioxolyl, benzodioxanyl and coumaranyl radicals, and physiologically tolerable acid addition salts thereof.
The compounds of the general formula I are new and they were prepared according to the following methods which are all included in the present invention.
The present invention provides a process for preparing a compound of the general formula I which comprises:
condensing a halo compound of the general formula II: ##STR6## in which A has the meaning given above and Hal is a chlorine or a bromine atom, with a N-monosubstituted piperazine of the general formula III: ##STR7## in which X, Y and R have the meanings given above; or condensing a halo compound of the general formula IV: ##STR8## in which X, Y, R and Hal have the meanings given above, with a N-monosubstituted piperazine of the general formula V: ##STR9## in which A has the meaning given above.
The above processes are advantageously carried out in solution in a polar solvent, for example an alcohol having a high boiling point, for example butanol or pentanol, or preferably an aliphatic amide, for example dimethyl formamide. The processes are advantageously carried out at a temperature of from 110° to 140° C. in the presence of an acceptor for the hydrogen halide formed in the course of the reaction. As acceptors, there may be mentioned, for example, alkali metal and alkaline-earth metal salts of carbonic acid, for example sodium and potassium bicarbonates and carbonates and calcium carbonate, and organic bases for example dimethylamine, pyridine and triethylamine; if desired, there may be used an excess of the monosubstituted piperazine of the formula III or V, the excess acting as the acid acceptor.
The present invention also provides a process for preparing a compound of the general formula I which comprises submitting a mixture of an aldehyde of the general formula VI: ##STR10## in which A has the meaning given above, and a N-monosubstituted piperazine of the general formula III given above, to an alkylating reduction using hydrogen at a pressure of from 5 to 7 atmospheres, in the presence of a small quantity of palladium-on-charcoal in a slightly polar aprotic solvent, for example, ethyl acetate.
Such a process is advantageously carried out by submitting to hydrogenation under a hydrogen pressure of from 5 to 7 atmospheres, a substantially equimolecular mixture of the compounds of the formulae III and VI, in solution in ethyl acetate, in the presence of a quantity of palladium-on-charcoal such that the weight of palladium is from 0.15 to 0.2% of the total weight of the reactants of the formulae III and VI at a temperature of from 50° to 80° C.
The starting materials used for these processes are known compounds, or they may be prepared according to methods described in the literature for preparing similar compounds, as mentioned in the following examples.
The compounds of the general formula I are weak bases which may be converted by treatment with acids into acid addition salts. As acids which may be used for the formation of these addition salts, there may be mentioned for example, in the mineral series: hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and in the organic series: acetic, propionic, maleic, fumaric, tartaric, citric, oxalic, benzoic, methanesulphonic and isethionic acids.
The compounds of the formula I may be purified by physical methods, for example by distillation, crystallization or chromatography, or by chemical methods, for example by formation of an addition salt followed by crystallization of the latter and decomposition thereof with an alkaline agent.
The compounds of the general formula I possess valuable pharmacological and therapeutic properties, especially anti-hypertensive, peripheral vasodilating, dopaminergic agonistic and anti-Parkinson properties. They may therefore, be used as medicines, especially in the treatment of hypertension, peripheral vascular disorders and Parkinson's disease.
Their toxicity is low and their LD50 determined in mice by intraperitoneal route is higher than 200 mg/kg.
Their neurologic properties were evidenced in the rats and mice by modifications observed on the stereotypy, motility and excitation.
In mice, the average effective dose is about 50 mg/kg by intraperitoneal route. At this dose, there were observed a decrease of motility and tonus.
The scores of CNS stimulation or stereotypy were determined according to the method of Quinton and Halliwell, Nature 200 No. 4902, p. 178 (1963). The scores for 3 hours raised up to 246 with a dose of 40 mg/kg I.P. and up to 261 with a dose of 80 mg/kg I.P.
Furthermore, when administered to the dog intravenously at doses of 0.5 to 2 mg/kg, an increase of the femoral output of up to 40% is observed durably.
The present invention therefore provides a pharmaceutical composition comprising as active ingredient a compound of the general formula I or a physiologically tolerable acid addition salt thereof in admixture or conjunction with a pharmaceutically suitable carrier, such for example, as distilled water, glucose, lactose, starch, talc, magnesium stearate, ethyl cellulose or cocoa butter.
The so-obtained pharmaceutical compositions are advantageously in unit dosage form and may contain from 30 to 100 mg of the active ingredient.
These pharmaceutical compositions may be in form of tablets, dragees, capsules, suppositories, injectable or drinkable solution and may be administered by oral, rectal or parenteral route at a dose of 30 to 100 mg, 1 to 5 times a day.
The following examples illustrate the invention, the melting points being determined in a capillary tube.
EXAMPLE 1 1-piperonyl-4-(1,3,4-thiadiazol-2-yl) piperazine ##STR11## First method
To a solution of 5.1 g (0.03 mole) of piperonyl chloride (cf. French Patent No. 1,312,427) in 60 ml of dimethylformamide, there were added 7.3 g (0.03 mole) of 1-(1,3,4-thiadiazol-2-yl)-piperazine dihydrochloride (melting at 220° C. with decomposition) and 6.4 g (0.06 mole) of dried sodium carbonate.
The reaction mixture was heated at 120° C. for 10 hours. Then, the sodium chloride formed was filtered off and the dimethylformamide was evaporated off under reduced pressure. The residue was taken up in 100 ml of benzene and 100 ml of water; the organic layer was decanted off and the solvent was evaporated off under reduced pressure. There were obtained 10 g of crystals which were recrystallized from 20 ml of ethanol. There were finally obtained 5.6 g of 1-piperonyl-4-(1,3,4-thiadiazol-2-yl)-piperazine melting at 111°-112° C.
The starting 1-(1,3,4-thiadiazol-2-yl)-piperazine was prepared by hydrolyzing with alcoholic potassium hydroxide the crude formyl derivative, itself prepared by condensing 1-formyl piperazine with 2-bromo-1,3,4-thiadiazole melting at 74° C. (Goerdeler and al., Ber 89 1534 (1956)).
Second method
A solution of 11.2 g (0.0678 mole) of 2-bromo-1,3,4-thiadiazole and 29.8 g (0.136 mole) of 1-piperonyl piperazine (cf. French Patent No. 1,312,427) in 400 ml of anhydrous dimethylformamide was heated at 110° C. for 8 hours. Then, the solvent was evaporated off under reduced pressure and the oily residue was taken up in 200 ml of benzene and 400 ml of water. The organic layer was decanted off then concentrated under reduced pressure. There was obtained a crystalline residue which recrystallized from 60 ml of ethanol, gave 9.9 g of crystals of 1-piperonyl-4-(1,3,4-thiadiazol-2-yl)-piperazine, melting at 112°-114° C.
Third method
A solution of 15 g (0.1 mole) of 3,4-methylenedioxybenzaldehyde and 24.3 g (0.1 mole) of 1-(1,3,4-thiadiazol-2-yl)-piperazine in 150 ml of ethyl acetate was hydrogenated under a hydrogen pressure of from 5 to 7 atmospheres, in the presence of from 2 to 5 g of palladised charcoal containing 10% of palladium, at a temperature of 50° C.
After absorption of the theoretical amount of hydrogen, the catalyst was filtered off and the solvent was evaporated off under reduced pressure.
There were obtained 27 g of a crystalline residue which, recrystallized from 150 ml of ethanol, gave 17 g of 1-piperonyl-4-(1,3,4-thiadiazol-2-yl) piperazine, melting at 112° C.
EXAMPLES 2 to 19
The following compounds were prepared according to the processes described in Example 1:
2. 1-(2-naphthylmethyl)-4-(1,3,4-thiadiazol-2-yl)-piperazine, M.P. 110°-112° C. (ethanol) starting from:
2-bromomethylnaphthalene and 1-(1,3,4-thiadiazol-2-yl)-piperazine, or
1-(2-naphthylmethyl)-piperazine and 2-bromo-1,3,4-thiadiazole, or
β-naphthaldehyde and 1-(1,3,4-thiadiazol-2-yl)-piperazine.
3. 1-(3,4-ethylenedioxybenzyl)-4-(1,3,4-thiadiazol-2-yl)-piperazine, M.P. 116°-117° C. (ethanol) starting from:
3,4-ethylenedioxybenzyl chloride (cf. French Patent No. 1,311,316) and 1-(1,3,4-thiadiazol-2-yl)-piperazine, or
1-(3,4-ethylenedioxybenzyl)-piperazine (cf. French Patent No. 1,311,316) and 2-bromo-1,3,4-thiadiazole, or
3,4-ethylenedioxybenzaldehyde (cf. Tomita, Chem. Abstracts 51 14728 (1957) and 1-(1,3,4-thiadiazol-2-yl)-piperazine.
4. 1-(5-coumaranylmethyl)-4-(1,3,4-thiadiazol-2-yl)-piperazine, M.P. 103°-104° C. (ethanol) starting from:
5-coumaranylmethyl chloride (cf. Baddeley and al. Soc. (1956) 2458) and 1-(1,3,4-thiadiazol-2-yl) piperazine, or
1-(5-coumaranylmethyl)-piperazine (prepared according to the method of Steward and al. J. Org. Chem. 13, 134 (1948)) and 2-bromo-1,3,4-thiadiazole, or
5-coumaranaldehyde (preparing according to Baddeley and al. Soc. (1956) 2458) and 1-(1,3,4-thiadiazol-2-yl)-piperazine.
5. 1-(5-coumaranylmethyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine, M.P. 116°-118° C. (ethanol), starting from:
5-coumaranylmethyl chloride and 1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine, or
1-(5-coumaranylmethyl)-piperazine and 5-methyl-2-bromo-1,3,4-thiadiazole, or
5-coumaranaldehyde and 1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine.
6. 1-(5-benzo [b] thienylmethyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine, M.P. 134°-136° C. (ethanol) starting from:
5-benzo [b] thienylmethyl bromide (cf. Y. Matsuki and al. Chem. Abstracts 65 15301 (1966)) and 1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine, or
1-(5-benzo [b] thienylmethyl)-piperazine (prepared according to the method of Steward and al. J. Org. Chem. 13 134 (1948)) and 5-methyl-2-bromo-1,3,4-thiadiazole, or
5-benzo [b] thienyl aldehyde (cf. Swiss Patent No. 442,353) and 1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine.
7. 1-piperonyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine, M.P. 88°-90° C. (purified by liquid chromatography) starting from:
piperonyl chloride and 1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine, or
1-piperonyl-piperazine and 5-methyl-2-bromo-1,3,4-thiadiazole, or
3,4-methylenedioxybenzaldehyde and 1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine.
8. 1-(3,4-ethylenedioxybenzyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine, M.P. 110°-111° C. (purified by liquid chromatography) starting from:
3,4-ethylenedioxybenzyl chloride and 1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine, or
1-(3,4-ethylenedioxybenzyl)-piperazine, and 5-methyl-2-bromo-1,3,4-thiadiazole, or
3,4-ethylenedioxybenzaldehyde and 1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperazine.
9. 1-(3,4-trimethylenedioxybenzyl)-4-(1,3,4-thiadiazol-2-yl)-piperazine, M.P. 104°-107° C. (acetonitrile/petroleum ether), starting from:
3,4-trimethylenedioxybenzyl chloride and 1-(1,3,4-thiadiazol-2-yl)-piperazine, or
1-(3,4-trimethylenedioxybenzyl)-piperazine and 2-bromo-1,3,4-thiadiazole, or
3,4-trimethylenedioxybenzaldehyde and 1-(1,3,4-thiadiazol-2-yl)-piperazine.
10. 1-(5-benzo [b] furanylmethyl)-4-(1,3,4-thiadiazol-2-yl)-piperazine, M.P. 98°-99° C. (purified by liquid chromatography), starting from:
5-benzo [b] furanylmethyl chloride (cf. A. Areschka and al. Chim. Therap. 7, 337 (1972)) and 1-(1,3,4-thiadiazol-2-yl)-piperazine, or
1-(5-benzo [b] furanylmethyl)-piperazine (prepared according to the method of Steward and al. J. Org. Chem. 13 134 (1948)) and 2-bromo-1,3,4-thiadiazole, or
5-benzo [b] furanyl aldehyde (cf. Glodenberg and al. Chim. Therap. 1, 221 (1966)) and 1-(1,3,4-thiadiazol-2-yl)-piperazine.
11. 1-piperonyl-4-(1,2,4-triazol-3-yl)-piperazine, starting from:
piperonyl chloride and 1-(1,2,4-triazol-3-yl)-piperazine, or 1-piperonyl-piperazine and 3-bromo-1,2,4-triazole (cf. Manchot and Noll, Lieb. Ann. 343 9 (1905)), or 3,4-methylenedioxybenzaldehyde and 1-(1,2,4-triazol-3-yl)-piperazine.
12. 1-(3,4-ethylenedioxybenzyl)-4-(1,2,4-triazol-3-yl)-piperazine, starting from:
3,4-ethylenedioxybenzyl chloride and 1-(1,2,4-triazol-3-yl)-piperazine, or
1-(3,4-ethylenedioxybenzyl)-piperazine and 3-bromo-1,2,4-triazole, or
3,4-ethylenedioxybenzaldehyde and 1-(1,2,4-triazol-3-yl)-piperazine.
13. 1-piperonyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-piperazine, M.P. 225°-227° C. (methanol), starting from: piperonyl chloride and 1-(3-methyl-1,2,4-oxadiazol-5-yl)-piperazine, or
1-piperonyl-piperazine and 3-methyl-5-chloro-1,2,4-oxadizole (cf. C. Mousseboy and Eloy, Helv. 47 838 (1964)), or
3,4-methylenedioxybenzaldehyde and 1-(3-methyl-1,2,4-oxadiazol-5-yl)-piperazine.
14. 1-(3,4-ethylenedioxybenzyl)-4-(3-methyl-1,2,4-oxadiazol-5-yl)-piperazine, M.P. 101°-102° C., starting from:
3,4-ethylenedioxybenzyl chloride and 1-(3-methyl-1,2,4-oxadiazol-5-yl)-piperazine, or
1-(3,4-ethylenedioxybenzyl)-piperazine and 3-methyl-5-chloro-1,2,4-oxadiazole, or 3,4-ethylenedioxybenzaldehyde and 1-(3-methyl-1,2,4-oxadiazol-5-yl)-piperazine.
15. 1-piperonyl-4-(1,2,4-thiadiazol-5-yl)-piperazine, M.P. 74° C. (ethanol), starting from:
piperonyl chloride and 1-(1,2,4-thiadiazol-5-yl)-piperazine, or
1-piperonyl piperazine and 5-bromo-1,2,4-thiadiazole (cf. J. Goerdeler and al. Ber. 90 182 (1957)), or
3,4-methylenedioxybenzaldehyde and 1-(1,2,4-thiadiazol-5-yl)-piperazine.
16. 1-piperonyl-4-(3-methyl-1,2,4-thiadiazol-5-yl)-piperazine, M.P. 110°-111° C. (acetonitrile), starting from:
piperonyl chloride and 1-(3-methyl-1,2,4-thiadiazol-5-yl)-piperazine, or
1-piperonyl piperazine and 5-chloro-3-methyl-1,2,4-thiadiazole, or
3,4-methylenedioxybenzaldehyde and 1-(3-methyl-1,2,4-thiadiazol-5-yl)-piperazine.
17. 1-(3,4-ethylenedioxybenzyl)-4-(3-methyl-1,2,4-thiadiazol-5-yl)-piperazine, M.P. 75°-76° C. (acetonitrile), starting from:
3,4-ethylenedioxybenzyl chloride and 1-(3-methyl-1,2,4-thiadiazol-5-yl)-piperazine, or
1-(3,4-ethylenedioxybenzyl)-piperazine and 5-chloro-3-methyl-1,2,4-thiadiazole, or
3,4-ethylenedioxybenzaldehyde and 1-(3-methyl-1,2,4-thiadiazol-5-yl)-piperazine.
18. 1-(3,4-ethylenedioxybenzyl)-4-(1,2,4-thiadiazol-5-yl)-piperazine, M.P. 146°-148° C. (ethanol), starting from:
3,4-ethylenedioxybenzyl chloride and 1-(1,2,4-thiadiazol-5-yl)-piperazine, or
1-(3,4-ethylenedioxybenzyl)-piperazine and 5-bromo-1,2,4-thiadiazole, or
3,4-ethylenedioxybenzaldehyde and 1-(1,2,4-thiadiazol-5-yl)-piperazine.
19. 1-piperonyl-4-(4-methyl-1,2,4-triazol-3-yl)-piperazine, M.P. 146°-148° C. (acetonitrile), starting from:
piperonyl chloride and 1-(4-methyl-1,2,4-triazol-3-yl)-piperazine, or
1-piperonyl piperazine and 4-methyl-3-bromo-1,2,4-triazole (cf. G. Barlin, Soc. (B) 1967 p. 641), or
3,4-methylenedioxybenzaldehyde and 1-(4-methyl-1,2,4-triazol-3-yl)-piperazine.
The following examples illustrate the pharmaceutical compositions containing as active ingredient, a compound of the general formula I.
EXAMPLE 20 Formulation for one injectable ampule containing 5 mg of active ingredient 
______________________________________                                    
1-(3,4-ethylenedioxybenzyl)-4-(1,3,4-thiadiazol-2-yl)-                    
piperazine methane sulfonate                                              
                            0.0065 g                                      
Mannitol                    0.050 g                                       
Distilled water for injectable preparation q.s.p.                         
                            2 ml                                          
______________________________________
EXAMPLE 21 Formulation for one injectable ampule containing 5 mg of active ingredient 
______________________________________                                    
1-(5-benzo [b] furanylmethyl)-4-(1,3,4-thiadiazol-2-yl)-                  
piperazine bis methane sulfonate                                          
                            0.0082 g                                      
Mannitol                    0.050 g                                       
Distilled water for injectable preparation q.s.p.                         
                            2 ml                                          
______________________________________
EXAMPLE 22 Formulation for one capsule containing 50 mg of active ingredient 
______________________________________                                    
1-piperonyl-4-(1,3,4-thiadiazol-2-yl)-piperazine                          
methanesulfonate          0.066 g                                         
Microcristalline cellulose                                                
                          0.082 g                                         
Carboxymethyl starch      0.006 g                                         
Colloidal silica          0.0005 g                                        
Talc                      0.0055 g                                        
______________________________________

Claims (7)

We claim:
1. A compound of the formula ##STR12## wherein the group ##STR13## is selected from the group consisting of naphthyl, benzo [b] furanyl, benzo [b] thienyl, benzodioxolyl, benzodioxanyl, benzodioxacycloheptanyl, coumaranyl, chromanyl, Δ3 -chromenyl, thiochromanyl and Δ3 -thiochromenyl.
2. A compound of claim 1, wherein ##STR14## is selected from the group consisting of benzo [b] furanyl, benzodioxolyl, benzodioxanyl and coumaranyl.
3. A compound of claim 1 which is 1-piperonyl-4-(1,3,4-thiadiazol-2-yl)-piperazine.
4. A compound of claim 1, which is 1-(3,4-ethylenedioxybenzyl)-4-(1,3,4-thiadiazol-2-yl)-piperazine.
5. A compound of claim 1, which is 1-(5-benzo [b] furanylmethyl)-4-(1,3,4-thiadiazol-2yl)-piperazine.
6. A pharmaceutical composition for treating peripheral vascular disorders or Parkinson's disease containing as active ingredient an effective amount of a compound of claim 1, together with a suitable pharmaceutically acceptable carrier.
7. A method for treating a living animal body afflicted with peripheral vascular disorders or Parkinson's disease, comprising the step of administering an effective amount of a compound of claim 1 for the alleviation of the said conditions.
US05/864,204 1976-12-31 1977-12-27 Disubstituted piperazines Expired - Lifetime US4177272A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4421753A (en) * 1982-01-15 1983-12-20 American Cyanamid Company 1-(5-Amino-4H-1,2,4-triazol-3-yl)-4-substituted-piperazines
US4613601A (en) * 1982-01-21 1986-09-23 Adir, S.A.R.L. (1-benzodioxin-6-ylmethyl)-4-substituted piperazines having antipsychotic activity
FR2799464A1 (en) * 1999-10-12 2001-04-13 Norchim Pure piperonyl-piperazine preparation in high yield, for use as drug intermediate, by reductive amination of piperonal with piperazine
WO2015140130A1 (en) * 2014-03-17 2015-09-24 Remynd Nv Oxadiazole compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2418798A1 (en) * 1978-03-03 1979-09-28 Science Union & Cie NEW DISUBSTITUTED PIPERAZINES, THEIR METHODS OF PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Citations (4)

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Publication number Priority date Publication date Assignee Title
US3489757A (en) * 1965-02-20 1970-01-13 Merck Ag E 1-alkylenedioxy aralkyl-4-(thiazolyl-2)-piperazines
US3808210A (en) * 1970-09-15 1974-04-30 Nom Coll Science Union Et Cie Naphthyloxy hydroxypropylamino-alkyl piperazines
US3917597A (en) * 1972-04-07 1975-11-04 Science Union & Cie Benzodioxole compounds
US3944551A (en) * 1973-04-02 1976-03-16 Science-Union Et Cie N-Coumaranyl and chromanyl -methyl-or sulfur analogs thereof-N'- thiazolyl piperazines

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3489757A (en) * 1965-02-20 1970-01-13 Merck Ag E 1-alkylenedioxy aralkyl-4-(thiazolyl-2)-piperazines
US3808210A (en) * 1970-09-15 1974-04-30 Nom Coll Science Union Et Cie Naphthyloxy hydroxypropylamino-alkyl piperazines
US3917597A (en) * 1972-04-07 1975-11-04 Science Union & Cie Benzodioxole compounds
US3944551A (en) * 1973-04-02 1976-03-16 Science-Union Et Cie N-Coumaranyl and chromanyl -methyl-or sulfur analogs thereof-N'- thiazolyl piperazines

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4421753A (en) * 1982-01-15 1983-12-20 American Cyanamid Company 1-(5-Amino-4H-1,2,4-triazol-3-yl)-4-substituted-piperazines
US4613601A (en) * 1982-01-21 1986-09-23 Adir, S.A.R.L. (1-benzodioxin-6-ylmethyl)-4-substituted piperazines having antipsychotic activity
FR2799464A1 (en) * 1999-10-12 2001-04-13 Norchim Pure piperonyl-piperazine preparation in high yield, for use as drug intermediate, by reductive amination of piperonal with piperazine
WO2015140130A1 (en) * 2014-03-17 2015-09-24 Remynd Nv Oxadiazole compounds
US10562869B2 (en) 2014-03-17 2020-02-18 Remynd Nv Oxadiazole compounds

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OA05840A (en) 1981-05-31
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PT67486A (en) 1978-01-01
PH14321A (en) 1981-05-27
AR217143A1 (en) 1980-02-29
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